First in human phase I / II clinical trial of RAFT for aniridia related keratopathy.

眼睛前表面的角膜是我们通向世界的窗口。如果透明度受损，可能会导致视力受损，甚至失明。无虹膜是一种罕见的致盲性疾病(发病率为1：10万)，由PAX6基因突变引起，PAX6基因是眼睛发育和健康功能的基因之一。无虹膜相关性角膜病变(ARK)表现为角膜外上皮层称为上皮的持续性、慢性疼痛的缺陷。血管长入角膜，也会形成疤痕，这两种情况都会阻碍视力。方舟诱导的光敏感会导致社会排斥。这些症状的原因与突变的角膜缘上皮干细胞(LESC)、基质细胞和组织无法维持正常的角膜上皮有关。目前的治疗方法包括全供体组织移植和培养的LESC治疗，这两种治疗方法都显示出较差的长期效果。由于干细胞需要环境中邻近细胞和蛋白质的支持，仅移植培养的LESC可能不足以保存/改善患者的视力。最佳的ARK治疗将包括移植健康的LESC和填充有基质细胞的基质(角膜支持组织)。我们建议的解决方案利用了我们的专利技术RAFT(Real Architecture For 3D Organities)，在该技术中，LESC和基质细胞在可移植的胶原基质(人造组织)中一起培养。在我们的临床细胞治疗生产实验室中，我们能够按照被称为良好生产实践或GMP的规定来制造这种组织。临床前安全性研究支持我们迈向人类研究的第一步。在这个项目中，我们将1)在我们的细胞中对ARK授权制造设施的RAFT进行全面的GMP协议验证，2)编写并提交获得监管部门批准的临床试验所需的所有文件，以及3)进行ARK患者的首个人类移植物移植研究。在这项I/II期临床试验中，我们将对21例ARK患者的一只眼进行RAFT移植，以评估RAFT的安全性和初步疗效。结果措施将包括恢复正常的角膜上皮，没有任何缺陷，血管植入或疤痕形成。如果成功，这种疗法可以为方舟患者提供急需的解决方案，并为开发治疗其他失明眼病的RAFT提供跳板。

The cornea on the front surface of the eye is our window to the world. If transparency is compromised, visual impairment and even blindness can occur. Aniridia is a rare blinding disease (1:100,000 incidence) caused by a mutation in PAX6 which is one of the genes responsible for development and healthy function of the eyes. Aniridia-related keratopathy (ARK) manifests as persistent, chronically painful defects of the outer epithelial layer of the cornea called the epithelium. Blood vessels grow into the cornea and scarring also occurs, both of which obstruct vision. ARK induced light sensitivity can lead to social exclusion. The cause of these symptoms is related to the inability of the mutated limbal epithelial stem cells (LESC), stromal cells and tissue to maintain normal corneal epithelium. Current treatments include whole donor tissue transplantation and cultured LESC therapy which have both shown poor long-term outcomes. Since stem cells require support from neighbouring cells and proteins in their environment, transplanting cultured LESC alone may not be sufficient to preserve / improve patient vision. An optimal ARK treatment would include transplantation of both healthy LESC and a stroma (corneal support tissue) populated with stromal cells. Our proposed solution utilises our patented technology known as RAFT (Real Architecture for 3D Tissues) in which LESC and stromal cells are cultured together in a transplantable collagen matrix (artificial tissue). We are able to make this tissue in compliance with the required regulations which are known as Good manufacturing practise, or GMP for short, in our clinical cell therapy production laboratory. Pre-clinical safety studies supports us moving forward to a first in human study. In this project we will undertake 1) full GMP protocol validation for RAFT in our Cells for Sight licensed manufacturing facility, 2) write and submit all of the documentation required to obtain regulatory approval for a clinical trial and 3) proceed to first in human RAFT transplantation studies in patients with ARK. In this phase I/II clinical trial we will perform RAFT transplantation in one eye of 21 ARK patients to assess RAFT safety and preliminary efficacy. The outcome measures will include restoration of a normal corneal epithelium without any defects, blood vessel ingrowth or scarring. If successful, this therapy could provide a much-needed solution for patients with ARK and also act as a springboard for the development of RAFT for other blinding eye diseases.